Methods for inhibiting aggressive behavior by means of s-triazolo-(3,4-a)-isoquinolines

ABSTRACT

CERTAIN S-TRIAZOLO-(3,4-A)-ISOQUINOLINE COMPOUNDS ARE SHOWN TO EXHIBIT ANTI-AGRESSIVE ACTIVITY. THE 8,9-DIMETHOXY AND 3-METHYL-8,9-DIMETHOXY DERIVATIVES ARE PREFERRED.

United States Patent Officc Patented July 17, 1973 3,746,714 METHODS FOR INHIBITING AGGRESSIVE BE- HAVIOR BY MEANS OF s-TRIAZOLO-[3,4-a]- ISOQUINOLINES Morton E. Goldberg, Glen Rock, N.J., assignor to Mallinckrodt Chemical Works, St. Louis, M0. N Drawing. Filed Oct. 6, 1971, Ser. No. 187,175 Int. Cl. A61u 27/00 US. Cl. 424-258 Claims ABSTRACT OF THE DISCLOSURE Certain s-triazolo-[3,4-a]-isoquinoline compounds are shown to exhibit anti-agressive activity. The 8,9-dimethoxy and 3-methyl-8,9-dimethoxy derivatives are preferred.

BACKGROUND OF THE INVENTION The present invention relates to the pharmaceutical field, and more particularly to methods and pharmaceutical compositions for treating mammals utilizing as active agents certain organic heterocyclic compounds from the class known as s-triazolo-[3,4-a]-isoquinolines.

The preparation of various s-triazolo-[3,4-a1-isoquinolines is disclosed by (1) S. Naqui et al., Indian J. Chem., 3, 162-4 (1965); (2) G. S. Sidhu et al., Jour. Heterocyclic Chem., 3, 158-164 (1966); (3) J. E. Francis, US. Pat. 3,354,164 (1967); (4) H. K. Reimlinger et al., French Pat. 1,573,135 (1969) and (5) H. K. Reimlinger et al., Chem. Ber. 103, 1960-1981 (1970).

No pharmaceutical compositions or utility are disclosed in preferences (1), (2), (4) and (5) cited above. Francis 3) discloses that unsubstituted s-triazolo-[3,4-a]-isoquinoline and its 3-lower alkyl derivatives are coronary vasodilators.

The invention is particularly concerned with the use of certain compounds for selectively inhibiting aggressive behavior in mammals.

It is known that certain compounds exhibit a type of central nervious system activity characterized as antiaggressive activity. For example, it has been previously reported that benzquinamide, a central nervious system depressant (Merck Index, Eight ed., p. 136), and tetrabenazine, an antipsychotic agent (Merck Index, Eighth ed., p. 1022) possess some degree of antiaggressive activity.

It has been confirmed that lesions in the septal region of the forebrain in rats produces a striking increase in emotional behavior. Brady et al., J. Comp. Physiol. psychol. 46, 339 (1953) and Brady et al., J. Comp. Physiol. Psychol. 48, 412 (1955). This is accompanied by violent attack behavior in response to previously neutral stimuli (septal rats). The effects of depressant compounds on this type of aggressive behavior have been reported, e.g., Hunt, N.Y. Acad. Sci., 67, 712 (1957), Randall et al., J. Pharmacol. exp. Ther. 129, 163 (1960) and Malick et al., Arch. int. Pharmacodyn. 181, 459 (1969). In addition, it has been shown (Karli, C. R. Soc. Biol. 149, 2227 (1955) and Karli, Behaviour, 10, 81 (1956) that certain rats will readily attack and kill mice upon presentation (killer rats). Here again, it has been demonstrated that certain antidepressants, stimulants and antihistaminics selectively inhibt the muricidal (mouse killing) response in these rats (Horovitz et al., Life Sci. 4, 1909 (1965) and Horovitz et al., Int. J. Neuropharmacol. 5, 405 (1966). So-called septal rats and killer rats procedures have thus been established to determine the inhibitory effect of test compounds on aggressive behavior (cf. Goldberg, Arch. int. Pharmacodyn., 186, 287 (1970).

SUMMARY OF THE INVENTION Among the several objects of the invention may be noted the provision of pharmaceutical compositions and methods for inhibiting aggressive behavior in a susceptible mammal, which compositions and methods utilize certain known s-triazolo-[3,4-a]-isoquinolines as active agents; and the provision of such compositions which are adapted for either oral or parenteral administration to such susceptible mammals. Other objects and features of the invention will be in part apparent and in part pointed out hereinafter.

The present invention is thus directed to a method of inhibiting aggressive behavior in a susceptible mammal by administering to said mammal an efiective amount of an s-triazolo-[3,4-a1-isoquinoline compound from the group hereinafter specifically set forth and to pharmaceutical compositions comprising such a compound and a pharmaceutical carrier.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with the present invention, it has now been found that certain s-triazolo-[3,4-a]-isoquinoline compounds exhibit anti-aggressive activity. The type and degree of anti-aggressive activity observed with s-triazolo- [3,4-a]-isoquinoline compounds is selective in nature and the presence or absence of such activity, and its degree when present, appears to be quite sensitive to the position and type of substitution on the basic s-triazolo[3,4-a]- isoquinoline structure.

The specific s-triazolo-[3,4-a]-isoquinoline compounds which have been found to possess anti-aggressive activity are: 8,9-dimethoxy-s-triazolo- [3 ,4-a] -isoquinoline 3-methyl-8,9-dimethoxy-s-triazolo- [3,4-a] isoquinoline 3-ethyl-8,9-dimethoxy-s-triazolo- [3,4a] -isoquinoline 3-isopropyl-8,9-dimethoxy-s-triazolo-[3,4-a]-isoquinoline 3,5-dimethyl-s-triazolo-[3,4-a]-isoquinoline 5 -methyl-s-triazolo- [3 ,4-a] -iso quinoline 3-(N-pyrrolidylmethyl)-s-triazolo-[3,4-a]-isoquinoline 3 -trifluoromethyl-6-chloro-s-triazolo- [3,4-a] -isoquinoline 7 -amino-s-triazolo- [3,4-a1-isoquinoline As brought out hereinafter, the compounds 8,9-dimethoxy-s-triazolo-[3,4-a] -isoquinoline and 3-methyl-8,9- dimethoxy-s-triazolo-[3,4-a] -isoquinoline have both been shown to specifically inhibit the aggressive response in mouse-killing and septal-lesioned rats at doses below those which produced evidence of neurotoxicity.

In further accordance with the invention, pharmaceutical compositions and methods useful in inhibiting aggressive behavior in susceptible mammals are provided, the compositions comprising an aforementioned s-triazolo- [3,4-a1-isoquinoline compound and a pharmaceutical carrier which may be either liquid or solid material. These compositions may be administered orally or parenterally in the usual pharmaceutical forms including capsules, tablets, solutions, suspensions and the like. For example, the s-triazolo-[3,4-a]-isoquinoline compound may be formulated with carriers such as magnesium stearate and lactose and filled into gelatin capsules. Examples of other solid pharmaceutical carriers, such as fillers, binders and lubricants, include dibasic calcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate and talc. The pharmaceutical compositions of the invention may also be in the form of sterile parenteral solutions with the s-triazolo-[3,4-a]-isoquinoline compound dissolved in a sterile parenteral solvent such as polyethylene glycol, propylene glycol, water or mixtures of solvents or the compositions may be in the form of suspensions.

Where the s-triazolo-[3,4-a1-isoquinoline compound is water-insoluble, it is preferred that the compound be formulated into the pharmaceutical compositions of the invention in a micronized form, as by milling the compound by conventional methods. More particularly, it is 4 EXAMPLE 2 The anti-aggressive activity of 3-ethyl-8,9-dimethoxys-triazolo-[3,4-a]-isoquinoline, 3,5 dimethyl-s-triazolo- [3,4-a]-isoquinoline and S-methyl-s-triazolo-[3,4-a1-isopreferred that the compound be mlcronrzed to a partlcle q hn w s detcrmlned usmg the ss size of approximately 1-10 microns. test P d The following examples illustrate the invention: The ammals were housed individually for pp In the following animal studies, male hooded rats of mately 6 Weeks and ntained On a restricted food inthe Long-Evans strain, weighing between 200 and 300 10 f e 0f grams P day of Solid food and Water ad grams and malg albino mice, weighing approximately l1b1tum. Atter isolation, thfi rats W6l'6 tStCd fOI thfill grams, were used as subjects. They were permitted food lhouse-klllmg {651101186 and y those animals Which and water ad libitum except during drug studies and kllled lnlce Wlthhl 2 minutes after Pfesfintatiofl 011 3 during the period in which killer rats were selected. consflcutlve y were llsfid- The Se ected animals were teste twice rior to tr tm t d t 30 60 120 180 15 p ea en an a EXAMPLE 1 and 240 minutes after intraperitoneal injection of the test The anti-aggressive activity of representative comcompound. The ED was obtained and is defined as that pounds of the invention was determined using the followdose which blocks attacks in 50% of the animals tested. mg septal rats test procedure. The ED values for 3-ethy1-8,9-dimethoxy-s-triazolo- Bilateral electrolytic lesioning, utilizing anodal DC cur- 20 [3,4-a]-isoquinoline, 3,5 dimethyl-s-triazolo-[3,4-a]-isorent, of the septal area was performed under pentobarbit'al quinoline and 5 methyl-s-triazolo'[ 3,4-a] isoquinoline anesthesia. The animals were stereotaxically lesioned, were found to be 17 mg./kg., 34.5 mg./kg. and 22.8 mg./ usmg a slight modification of the method of Stark and kg, respectively. Henderson (Int. H. NeuropharmacoL, 5, 385 (1966)), in which a current intensity of 7 milliamperes was delivered EXAMPLE 3 o 5 Seconds each septal region- All animals were The anti-aggressive activity of 8,9-dimethoxy-s-triazologrven penicillin prophylactically, and were mitially tested [3,4-a1-isoquinoline and 3-methyl-8,9-dimethoxy-s t i- 3 to 6 y after leSioning- The Kohig and PP l atlas azolo-[3,4-a]-isoquinoline was compared with that of (cf. The Rat Brain, Williams & Wilkins C0., Baltim r chlorpromazine, chlordiazepoxide, imipramine, tetra- Md., 1963) Was utilized for histological verification of benazine and benzquinamide. Chlorpromazine, chlordilesion sites in selected animals. A scoring system was used azepoxide and imipramine were used as hydrochloride which measured only the aggressiveness component of salts and tetrabenazine was used as the methanesulfonate the septal syndrome. The animals were tall restramed salt. The other compounds were used as bases. and evaluated before and 60 minutes after the mtra- The compounds were dissolved or finely suspended Peritoneal1 illlflction l of Oral administratioh 0f the in 0.5% methylcellulose solution just prior to use and compounds tested. Two inanimate objects, a pencil and a concentrations varied as to administer them in a conglove, were oflered and reacuons were graded as: 0 stant volume proportional to the weight of the animal. The md1tference t0 elther stlmul of one or doses reported below refer to the amount of base or to h l 2V0fa010 11S attack of 1 l f t the amount of salt given when used in that form. c1ous attack of both ob ects. Only rats which exhibited 40 Th .r

6 compounds were tested usmg the septal rats a score of 3 prior to m ection of a test compound were .t r as and killer rats procedures of Examples 1 and 2. In used, and ammals wh1ch showed a 0 or 1 score at retest the killer rats test to d th 1 t d (60 minutes post injection) were considered blocked. testedt Ce 6 some ammals.were The ED value was obtained for each compound tested wlce p 0 i f q and at 30 and 60 mmutes and is defined as that close which results in a score of after mtrapemoneal lfllfectlon of the test Fompound- The 0 1 in of the animals tested The following compounds were admmlstered by intrapentoneal injection sults were obtained: m each test- The compounds were also tested in accordance with TABLE 1 the following neurotoxicity or rotarod performance test 50 procedure. Rats were trained to maintain themselves on g gi g a slowly revolving wooden rod (5 rev./min.) according 2 ggg y to the method of Dunham and Miya, J. Amer. Pharm. As- Compound tration mgJkg.) soc. (Sci. ed.) 46, 208 (1957). They were tested prior to 3 athyl 8,9 mmethoxy s tmz01o [3,4 a] iS0 M and at 15, 30 and minutes after administration of the 1 m) lli ld 1m th 1 1 3+ 1 4 test compounds. Neurotox1c1ty was cons1dered when the i;tni) ri e. y e y )lsfl mm H a]- So' animals fell from the rotarod more than once during a one r minute period. Mean neurotoxic doses (NTD were calfimethyl'smmmla'ka]'isoqmmhm? "{Oral 10:9 culated at the post-drug period which yielded maximal 7-amino-s-triazolo-[3,4-a]-isoquinollne I.P 25 60 responses 1 pp y- The results are set forth in the following table.

TABLE 2 r NTD NTD iq 'ih ifls s d iiii Killer rats test, ED Se tal rats test, ED C nd mgJkg. CL.) mgJkg. EDso 95% C.L.) mgJkg. ED 1. 1.0-2.1 24 55.5 41.0-75.0 25) .03 1/0 at 30.0 (18) .05 3523 523353. 1.3%102. 1; E24; 5.t 3(2.6-12.3; $25) .34 11.a 7.9-1s.4) 21 .17 Bonzq r 6.8(4.310.7) 1s) 57.9(40.6-82.4) (1s) .12 26.4(14.6-47.9) 2s) .26 Ohlordiazepoxide 7.3(4.2-12-8) 1s) 20.5(13.s-30.5) 20) .36 23.0(14.4-36.8) (18) .32 8,9-dimethoxy-s-triialzolo-[3,4 n]-isoqllinollnm.lii ii (18) Y's-mama- 'ahsoq no me must-29:2; 24) 15.4 617-2618) 27 1172 52.0 4619-517) 20 .44

N orn.Number in parenthesis following (95% C.L.) refers to number of animals studied.

The NTD /ED ratios were obtained in order to examine the results for selectivity in accordance with the concept of Horovitz et al., Int. J. Neuropharmacol. 5, 405 (1966). Any ratio value greater than unity assumes selectivity for anti-aggressive activity compared with overt depression aond ataxia, as measured by the rotarod procedure. On this basis, 3-methyl-8,9-dimethoxy-s-triazolo- [3,4-a]-isoquinoline, 8,9-dimethoxy-s-triazolo-[3,4-a]isoquinoline and imipramine were found to be active selectively in the killer rats procedure and only the two aboveidentified triazoloisoquinoline compounds were considered selective in taming septal rats. None of the other compounds studied yielded a ratio greater than one in either procedure.

Each of the compounds was also tested in accordance with the following discrete avoidance behavior procedure to permit another evaluation of overt depression. Using an automated pole-climb procedure (Aceto et al. Arch. Int. -Pharmacodyn., 144, 214 (1963) and Johnson and Goldberg, J. Pharm. PharmacoL, 17, 55 (1965) a modification of the method of Cook and Weidley (Ann. N.Y. Acad. Sci., 66, 740 (1957)) was used to study discrete avoidance behavior. Groups of 6 rats each were trained in individual boxes to consistently avoid foot-shock by jumping onto a Plexiglas pole. After training, performance criteria were established with solvent injections. In each experimental week, animals were given a control session and drug-treatment session on successive days. Each 2 hour behavioral session contained 240 discrete trials, each consisting of a 15 second intertrial interval (no stimulus), 10 seconds of buzzer, followed by 5 seconds of buzzer +shock (1 ma.). A response made at anytime while the buzzer was on terminated the trial. Reaction latencies, which were indicative of the animal's response (avoidance, escape, no response), were printed out for each trial and averaged for the session. Avoidance efliciencies for each animal and for each group were averaged. All animals used in these studies showed mean control response latencies between 4 to 7 seconds and successfully avoided shock in 92% or more of the trials. To obtain an estimate of the IB (dose necessary to reduce response to 50% of control) and its 95% confidence limits (95% C.L.), a weighted linear regression analysis was used (Snedecor et al., Statistical Methods (Iowa State Coll. Press, Arnes, Iowa, 1967)).

The results are set forth in the following table:

NOTE.N11I11be1 in parenthesis following (95% (LL) refers to number of animals studied.

EXAMPLE 4 The anti-aggressive activity of S-methyl-s-triazolo-[3,4-

a]-isoquinoline was determined using the following iso lated fighting mice procedure.

The test animals were male mice which had been isolated in acage for three weeks. The mice were aggressive and would attack within 5 minutes a non-isolated male mouse placed in its cage. After interaction of 5 minutes, the second mouse is removed. If no fighting occurred during this interval, the isolated mouse was considered to have been rendered non-aggressive. The ED was obtained and is defined as that dose of the test compound which renders 50% of the animals tested non-aggressive. The ED for S-methyl-s-triazolo-[3,4-a]-isoquinoline was found to be approximately 12.8 mg./kg. for intraperitoneal injection.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

What is claimed is:

1. A method of inhibiting aggressive behavior in a susceptible mammal which comprises administering to said mammal an effective amount of a compound selected from the group consisting of 8,9-dimethoxy-s-triazolo- 3,4-a] isoquinoline,

3-methyl-8 ,9-dimethoxy-s-triazolo- [3 ,4-a] isoquinoline,

3-ethyl-8,9-dimethoxy-s-triaz0lo [3 ,4-a] isoquinoline,

3isopropyl-8,9-dimethoxy-s-triazolo- [3 ,4-a] isoquinoline,

3,5 dimethyl-s-triazolo- [3,4-a1-isoquinoline,

S-methyl-s-triazolo- [2,3-a] isoquinoline,

3- (N-pyrrolidylmethyl) s-triazolo- [3 ,4-a] isoquinoline,

3trifluoromethyl-6chloro-s-triazolo- [3 ,4-a] isoquinoline and 7-amino-s-triazolo- 3 ,4-a] isoquinoline.

2. A method as set forth in claim 1 wherein said compound is 8,9-dimethoxy-s-triazolo-[3,4-a]-isoquinoline.

3. A method as set forth in claim 1 wherein said compound is 3methyl-8,9-dimethoxy-s-triazolo-[3,4-a]-isoquinoline.

4. A method as set forth in claim 1 wherein said compound is 3ethyl-8,9 dimethoxy-s-triazolo-[3,4-a]-isoquinoline.

5. A method as set forth in claim 1 wherein said compound is 3-(N-pyrrolidylmethyl)s-triazolo-[3,4-a]-isoquinoline.

References Cited UNITED STATES PATENTS 3,354,164 11/1967 Francis 424258 OTHER REFERENCES Chem. Abst. 73-25363r (1970).

STANLEY T. FRIEDMAN, Primary- Examiner 

